We have recently made a novel discovery which supported a much earlier hypothesis, that activation of the hypothalamic-pituitary-adrenal axis may precede, rather than simply follow, opioid antagonist (eg. naloxoneprecipitated withdrawal in opioid dependent persons, whether they are persons receiving opioids on a chronic basis for the treatment of opiate addiction or for the management of chronic pain. In this study, which will be reported in Metabolism (Culpepper-Morgan, J and Kreek, MJ, Volume 46, February, 1997) we were able to document hypothalamic- pituitary-adrenal axis hypersensitivity in a patient with chronic pain management with chronic opioid agonist and thus, with opioid dependence. As part of a larger study on attempts to manage opioid-induced gastrointestinal motility disorders in patients receiving opioids on a chronic basis, a titration study was conducted in which small amounts of the opioid antagonist naloxone, which has extremely limited systemic bioavailability after oral administration, was administered in incremental doses on separate days. Both clinical symptoms and signs of opiate withdrawal, including both adrenergic and opioidergic signs of withdrawal, as well as objective measurements of hormones of the hypothalamic- pituitary-adrenal axis were assessed. It was found that objective changes in the hypothalamic-pituitary-adrenal axis preceded the onset or appearance of clinical signs and symptoms of withdrawal and in fact, at some low doses, occurred in the absence of any clinical signs or symptoms of withdrawal. Also, plasma levels of naloxone were strongly correlated with plasma cortisol levels. Neuroendocrine changes reflecting activation of the hypothalamic- pituitary-adrenal axis persisted long after the adrenergic changes in clinical symptoms had ameliorated, either spontaneously or by administration of a short-acting opioid antagonist. This study suggests that the hypothalamic- pituitary-adrenal axis is a more sensitive indicator of opioid withdrawal than the adrenergic system. Moreover, it suggests that activation of the stress- responsive hypothalamic-pituitary-adrenal axis may contribute to or cause many of the changes seen in both acute opiate withdrawal and possibly contribute to the protracted abstinence syndrome. These findings have potentially enormous implications both in the management of pain and also in the management of opiate addiction. In the management of chronic pain, especially in the setting of the potential for eliminating opioid agonist treatment, an understanding of the role of the activation of the hypothalamic- pituitary-adrenal axis in the signs and symptoms of opiate withdrawal may allow new approaches to be targeted to preventing or attenuating such activation. Similarly, in the management of short-term opiate addiction, where so-called "detoxification" treatments of either the pharmacological or nonpharmacological type may be indicated, again, increased information about the role of activation of the stress-responsive hypothalamic-pituitary- adrenal axis may be of value in developing new therapeutic innovations. Of possibly greatest importance are the implications of these findings for the understanding of both drug craving or drug hunger, and also the high propensity to relapse in medication-free former opiate-dependent persons. These are novel findings which may ultimately lead to improvement of therapeutic approaches both for the management of short-term and long-term addiction and the management of patients with chronic pain requiring opioid agonist treatment.